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Mechanism of the initiation of mRNA decay: role of eRF3 family G proteins

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Abstract mRNA decay is intimately linked to and regulated by translation in eukaryotes. However, it has remained unclear exactly how mRNA decay is linked to translation. Progress has been made in recent years in understanding the molecular mechanisms of the link between translation and mRNA decay. It has become clear that the eRF3 family of GTP‐binding proteins acts as signal transducers that couple translation to mRNA decay and plays pivotal roles in the regulation of gene expression and mRNA quality control. During translation, the translation termination factor eRF3 in complex with eRF1 recognizes the termination codon which appears at the A site of the terminating ribosome. Depending on whether the termination codon is normal (bona fide) or aberrant (premature), deadenylation‐dependent decay or nonsense‐mediated mRNA decay (NMD) occurs. mRNA without termination codons and mRNA with the propensity to cause the ribosome to stall are recognized as aberrant by other members of the eRF3 family during translation, and these translational events cause nonstop mRNA decay (NSD) and no‐go decay (NGD), respectively. In this review, we focus on how mRNA decay is triggered by translational events and summarize the initiation mechanism for the decay of both normal and aberrant mRNAs. WIREs RNA 2012. doi: 10.1002/wrna.1133 This article is categorized under: Translation > Translation Mechanisms RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability

eRF3 family GTP‐binding proteins. The family members share a common domain structure, with an amino‐terminal domain of ∼200 amino acids unique to each member and a carboxy‐terminal eEF1A‐like structure. Shown are the structures of human eRF3a, eRF3b, Hbs1, GTPBP1, GTPBP2, and yeast Ski7.

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eRF3 family G proteins and mRNA decay. eRF3 family G proteins play key roles in triggering the decay of both general and aberrant mRNAs in a manner coupled to translation termination. In general, eRF3 mediates translation termination at the bona fide termination codon to trigger deadenylation. In nonsense‐mediated mRNA decay, eRF3 mediates translation termination at a premature termination codon to trigger endonucleolytic cleavage (metazoa) or decapping (yeast). In nonstop mRNA decay, Ski7 and/or Hbs1 mediate translation termination at the 3′ end of nonstop mRNA to trigger exosome‐catalyzed 3′ to 5′ degradation. In no‐go decay, Hbs1 mediates translation termination at the stalled ribosome to trigger endonucleolytic cleavage.

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Initiation mechanisms for nonstop mRNA decay (NSD) and no‐go decay (NGD). (a) NSD: When a transcript lacking the termination codon is translated, the ribosome enters to translate the 3′ poly(A) tail of the mRNA and stalls at the 3′ end. Ski7 and/or Hbs1‐Dom34 recognizes the empty A site of the ribosome, thereby releasing the ribosome. Ski7 recruits exosome to degrade the transcript in the 3′ to 5′ direction. (b) NGD: When a transcript with the structural propensity to cause the ribosome to stall is translated, Hbs1–Dom34 recognizes the A site of the stalled ribosome and the transcript is endonucleolytically cleaved by an unknown nuclease. Hbs1–Dom34 releases the stalled ribosome.

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What determines whether translation termination triggers deadenylation‐dependent decay or nonsense‐mediated mRNA decay (NMD)? (a) General mRNA decay: At the bona fide termination codon, eRF3 can interact with poly(A)‐binding protein (PABP), thereby triggering deadenylation‐dependent decay (as shown in Figure 5). (b) NMD: At the premature termination codon, which is far from the 3′ poly(A) tail, the interaction between eRF3 and PABP is less efficient. eRF3 thus binds to Upf1 instead of PABP, and triggers NMD rather than deadenylation‐dependent decay (as shown in Figure 7).

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Initiation mechanism for nonsense‐mediated mRNA decay. When the translating ribosome reaches the premature termination codon, the termination factors eRF3–eRF1 in complex with Upf1 recognizes the termination codon at the A site of the ribosome. SMG1 catalyzes phosphorylation of Upf1. Exon junction complex, which is usually displaced by the translating ribosome, remains associated with the nonsense‐containing mRNA downstream of premature termination codon and enhances the phosphorylation of Upf1. The phosphrylated Upf1 recruits SMG6 to endonucleolytically cleave the message.

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Initiation mechanism for transcript‐specific mRNA decay; Tob‐mediated mRNA decay. In most mRNA, Tob mediates recruitment of Caf1–Ccr4 to the general RNA‐binding protein PABP, and translation termination triggers the recruitment and slow deadenylation. In transcript‐specific mRNA decay, however, Tob mediates recruitment of Caf1 deadenylase to the sequence‐specific RNA‐binding protein CPEB to negatively regulate its gene expression by accelerating deadenylation. As illustrated by the CPEB‐target mRNA, cis‐acting elements in the 3′ untranslated region and their trans‐acting factors can dominantly regulate the half‐life of the mRNA.

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Proposed model for the initiation of mRNA decay. The translation termination factor eRF3–eRF1 and the two major mRNA deadenylase complexes Caf1–Ccr4 and Pan2–Pan3 have poly(A)‐binding protein (PABP)‐binding motifs (PAM2) in common and competitively bind to PABP. After or during translation termination, eRF1–eRF3 dissociates from PABP bound to the poly(A) tail, and in turn, Pan2–Pan3 or Caf1–Ccr4 associates with PABP. This leads to the activation of the deadenylases and thus the poly(A) tail is shortened during translation. Although multiple PABP molecules are associated with the poly(A) tail, the illustrated model is simplified by drawing the only one PABP molecule.

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mRNA decay pathway of general mRNA. The first step of mRNA decay is the shortening of the 3′ poly(A) tail. The step called deadenylation is the rate‐limiting step of mRNA decay. The two major mRNA deadenylase complexes Pan2–Pan3 and Caf1–Ccr4 sequentially catalyze the reaction. After poly(A) tails are shortened to ∼10 nucleotides, decapping activators consisting of Lsm1–7, Dhh1/Rck, Pat1, Edc3, and Hedls etc. bind to the 3′ terminus and recruit the decapping enzyme Dcp1–Dcp2 to the 5′ terminus, which is associated with the 3′ terminus by the formation of a closed‐loop structure of the mRNA (Figure 2). The Lsm–Pat1–Dhh1 complex formed at the 3′ terminus blocks exonucleolytic degradation from the 3′ terminus by the exosome, and Xrn1‐catalyzed 5′ to 3′ decay proceeds as the major decay pathway. The 5′ to 3′ decay pathway enables even the last translating ribosome to produce a full‐length intact protein. Alternatively, a 3′ to 5′ decay pathway is also known.

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mRNA closed‐loop structure. eIF4E bound to the 5′ cap and PABP bound to the 3′ poly(A) tail form a complex with the scaffold protein eIF4G. This leads to the formation of a closed‐loop structure of mRNA. The binding of eRF3 to PABP could further loop‐out the long 3′ untranslated region of the mRNA and place the termination site in the vicinity of the initiation site, thereby contributing to translation by efficiently recruiting the terminating ribosome to the next round of translation initiation.

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Life‐cycle of an mRNA. After transcription, splicing and pre‐mRNA processing including capping and polyadenylation in the nucleus, mRNA matures and is transported to the cytoplasm, where translation occurs. mRNA decay also occurs while translation proceeds. In the first step of mRNA decay, the 3′ poly(A) tail is shortened co‐translationally. Subsequent processes including decapping and 5′ to 3′ decay of the deadenylated mRNA also occur on the polysome. In some cases, deadenylated mRNA could be transported to cytoplasmic granules called ‘P bodies’ and be stored, returned for translation or degraded.

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RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Turnover and Surveillance > Regulation of RNA Stability
Translation > Translation Mechanisms

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